Cardiovascular Diseases in Chronic Inflammatory Disorders
Inflammation plays a crucial role in the process of atherogenesis.1 Cardiovascular disease (CVD) is a major cause of mortality and morbidity in patients with chronic inflammatory disorders, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), chronic human immunodeficiency virus (HIV) infection, and psoriasis.2,3 Patients with chronic inflammatory diseases have an increased risk of coronary heart disease (CHD), stroke, peripheral vascular disease (PVD), and cardiomyopathy that may not be fully captured by traditional CVD risk factors, such as dyslipidemia, aging, hypertension, and smoking.4
The established and earlier concept that passive deposition of lipids into arterial walls with subsequent covering of the deposits by smooth muscle and endothelial cells causes atherosclerosis has changed over the course of time.5 Contribution of the immune system to all phases of atherogenesis, including well-known inflammatory reactions consequent to intimal trapping and oxidation of low-density lipoprotein (LDL) cholesterol, have become increasingly evident.6 Besides atherosclerosis there has been a growing understanding of how chronic inflammation contributes to cardiomyopathy. Several randomized controlled trials have shown that an anti-inflammatory regimen may produce an improvement in left ventricular ejection fraction (LVEF) in certain subpopulations of idiopathic dilated cardiomyopathy patients.7-9 Therefore, targeting inflammatory pathways to curb the risk of CHD could prove to be a decisive preventive strategy. In this review, we summarize human inflammatory disease states that are associated with accelerated CHD.
Rheumatoid Arthritis and Cardiovascular Disease
RA is a chronic inflammatory disease of joints associated with increased mortality rates compared to the general population, with standardized mortality ratios between 1.3 and 2.3.10 Premature CVD is a contributor to the widened mortality gap observed between RA and non-RA population.11
Meta-analysis of 14 studies including 41,490 patients demonstrated a 48% increased risk of first ever cardiovascular events (CVE) in patients with RA compared to the general population. The risks for myocardial infarction (MI) and stroke were higher by 68% and 41% respectively.12 There was also a three-fold increase reported for carotid atherosclerosis in RA patients despite a more favorable risk factor profile.13 Notably, the increased incidence rates of CVEs in RA patients are independent of traditional CVD risk factors. Increased CV risk in RA patients is associated with accelerated atherosclerosis, endothelial dysfunction and changes in LV geometry. Due to these changes, combined circumferential and longitudinal LV systolic dysfunction is detectable in about one quarter of patients with asymptomatic RA despite preserved LVEF and is associated with LV concentric hypertrophy and remodeling.14
The immunopathology of RA is complicated, and it shares some common systemic inflammatory components with atherosclerosis. Large prospective cohort studies have shown benefit for anti-inflammatory therapies in reducing CVD risk in RA patients supporting the role of chronic inflammation in development of CHD in RA.15,16 Multiple animal studies have confirmed the atherogenic role of circulating activated immune cells and elevated inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-7) in RA.17,18 Targeting these cytokines may reduce not only the atherosclerotic burden, but also may reduce the inflammatory quality of the existing plaques.17
Psoriasis and Cardiovascular Disease
Psoriasis, one of the most common immune-mediated skin diseases, affects approximately 25 million people in North America and Europe. Despite increased prevalence of CVD risk factors, psoriasis is associated with increased vascular inflammation beyond cardiovascular risk factors.19-23 It also confers an independent risk for atherosclerosis, MI, stroke, and PVD.24-29 Psoriasis and atherosclerosis have common inflammatory pathways involving helper T cells type 1 (Th1) and 17 (Th17) that play an integral role in disease pathogenesis and progression. This may explain the increased risk of heart disease in psoriasis patients.30
Furthermore, psoriasis patients have increased risk of developing cardiomyopathy and heart failure (HF). A large cohort study demonstrated a significant dose-dependent relationship between psoriasis skin disease severity and new-onset clinical HF, with hazard ratios (HR) of 1.22 for mild and 1.53 for severe disease.31
A recent meta-analysis of seven observational studies including RA and psoriasis patients revealed that low dose methotrexate predicted a lower risk of CVEs and vascular inflammation.32 However, effect of methotrexate on vascular inflammation needs further exploration. Ongoing RCTs, such as the Vascular Inflammation in Psoriasis Trial (VIP), will test the impact of aggressive anti-inflammatory skin disease treatment on vascular disease in psoriasis.
Systemic Lupus Erythematosus and Cardiovascular Disease
SLE is an inflammatory autoimmune disease with a wide range of clinical manifestations and complications. Owing to improved and evolving clinical practice patterns over the last few decades, and the long-term survival of patients with SLE, CVD has become a leading cause of death.33 SLE patients have accelerated atherosclerosis that is not explained by traditional risk factors, and it is not limited to one vascular territory but actually overlaps between the coronary, carotid, and lower-extremity arteries.4,34 There is an increased risk of coronary artery disease (CAD), stroke, and peripheral arterial occlusive disease (PAOD) in SLE.4,35,36 A meta-analysis of 80 studies revealed increased carotid intima media thickness and carotid atherosclerosis in SLE patients compared to control population.37 Contrary to RA, SLE patients have subclinical LV deformation and impairment even with normal ejection fraction. In fact, there is a negative correlation between lupus activity and LV systolic strain.38
Multiple SLE-specific mechanisms such as auto-antibodies, raised inflammatory cytokine levels, endothelial cell dysfunction, vascular wall inflammation, and dyslipidemia also promote and accelerate atherosclerosis progression.29 Many SLE treatments reduce vascular inflammation and the risk of thrombo-occlusive events. Hydroxychloroquine, one of the common medications used to treat lupus, disrupts the production of IFNα, an inflammatory cytokine involved in endothelial cell dysfunction.40 Rituximab, a biological therapy, decreases inflammation by depleting B cells, and also results in improved lipid profile by reducing total cholesterol and triglycerides, and increasing high-density lipoprotein (HDL) cholesterol.41,42
Systemic Sclerosis and Cardiovascular Disease
SSc is a systemic autoimmune disease of unknown etiology associated with increased mortality, particularly due to cardiopulmonary complications.43 However, it is unclear whether accelerated atherosclerosis occurs in SSc. Studies designed to investigate the risk of subclinical atherosclerosis in scleroderma patients revealed equivocal findings.44 In a recent case-control study using carotid plaque as an outcome for atherosclerosis, SSc patients had 19.1% increase in subclinical atherosclerosis compared to 3% in healthy controls.45 Another large cohort study of 1239 SSc patients revealed a 13/1000 person-years incidence rate for myocardial infarction versus 4.1/1000 person-years in the comparison cohort with highest risk for MI within the first year of diagnosis.46 Additionally, SSc patients have impaired myocardial function, reduced RV contractility, RV diastolic dysfunction and alterations in LV contractility and diastolic function.47
Scleroderma vasculopathy can be explained by the vascular damage and endothelial cell activation due to increased vascular endothelial growth factor expression causing abnormal angiogenesis and circulating antibodies with anti-endothelial activity.48-50 However, larger studies investigating the mechanistic links between SSc and its vascular consequences are limited and should be carried out to further the knowledge in this aspect.
HIV and Cardiovascular Disease
An estimated 36.9 million people worldwide have HIV. In the past few years, as combination antiretroviral therapy availability has improved throughout the world, acquired immunodeficiency syndrome (AIDS) related deaths have also declined. HIV has transformed from a short-lived infection with high mortality to a virus-induced chronic disease with a chronic persistent inflammatory state characterized by persistent T-cell activation.
CVD has become one of the leading causes of non-AIDS-related morbidity and mortality.51 Patients with HIV have increased atherosclerotic CVD, predominantly subclinical atherosclerosis as shown by increased carotid intima-media thickness on ultrasound, greater risk of coronary artery atherosclerosis, and higher rates of subclinical myocardial inflammation on cardiac MRI.52-56 These measures serve as potential surrogates of increased CV morbidity and mortality observed in patients with chronic HIV infection. Moreover, HIV-associated cardiomyopathy is another known complication that can result from myocarditis, infiltration of myocardium with HIV virions, co-infection with other viruses (e.g., coxsackievirus B3, cytomegalovirus) or multifunctional inflammatory cytokine activation (such as TNF-a) by myocardial dendritic cells.57 Immune system deterioration affects CV outcomes in HIV patients. AIDS patients have increased in-hospital mortality due to acute myocardial infarction or stroke compared to HIV infected patients without AIDS.58
Accumulating evidence from epidemiology and human clinical research studies demonstrates that disease states known to harbor systemic inflammation elevate risk for CVD. Ongoing treatment trials of disease specific inflammation in RA, psoriasis, SLE, and HIV will inform whether curbing inflammation reduces CV morbidity and mortality. Furthermore, ongoing studies such as the Cardiovascular Inflammation Reduction Trial (CIRT) and the Cardiovascular Risk Reduction Study (CANTOS) will inform whether treatment of inflammation in those with known CVD (history of prior MI) will reduce future CV events. Regardless of the outcomes of these studies, knowledge of which pathways are involved in inflammatory atherogenesis will be augmented for future translational studies.
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- Parrillo JE, Cunnion RE, Epstein SE, et al. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 1989;321:1061-8.
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